A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis.
BACKGROUND
R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.


OBJECTIVE
To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide).


METHODS
The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.


RESULTS
Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week.


CONCLUSIONS
The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.
Veziris
Nicolas
N
Laboratoire de Bactériologie-Hygiène, Université Pierre et Marie Curie, Paris, France. nveziris@gmail.com
Ibrahim
Murad
M
Lounis
Nacer
N
Chauffour
Aurelie
A
Truffot-Pernot
Chantal
C
Andries
Koen
K
Jarlier
Vincent
V
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage; D000995:Antitubercular Agents / Q000008:administration & dosage*; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D008168:Lung / Q000378:metabolism; D051379:Mice; D011718:Pyrazinamide / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives; D014376:Tuberculosis / Q000188:drug therapy*
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; D011718:Pyrazinamide; C493870:bedaquiline; D012293:Rifampin; C018421:rifapentine